Neurodegenerative diseases are becoming more prevalent with the aging population. One particular neurodegenerative disease, which typically has its onset between the ages of 50 and 80 years of age is Parkinson's disease (PD). PD is a disorder of the brain which is characterized by tremor and difficulty with walking, movement, and coordination.
Parkinson's disease appears to be caused by a progressive deterioration of dopamine-containing neurons in the substantia nigra zona compacta of the brain. Dopamine (DA) is a chemical neurotransmitter, which is utilized by brain cells to transmit impulses to control or modulate peripheral muscle movement. The loss of dopamine-containing neurons results in reduced amounts of dopamine available to the body. This process is thought to disturb nerve cell function such that impulses are not transmitted properly, resulting in a loss of muscle control and function.
Currently, there is no known cure for PD. Treatments are typically aimed at controlling the PD symptoms, primarily by replacing the dopamine, either with L-DOPA which is metabolized to dopamine, or by administering chemical agents that stimulate the dopamine receptors. These receptors fall into two broad classes, D1-type and D2-type receptors. The former is divided into D1 and D5 receptors, while the D2 receptor family consists of D2, D3, and D4 receptors.
All major therapies for PD restore the DA tonus which is lost due to the progressive mesencephalic DA-ergic neurodegeneration. L-DOPA is a cheap and efficacious drug, but with a poor PK profile leading to dyskinesia and other response fluctuations. Selective D2-agonists (e.g. pramipexole) give less dyskinesia, and are the preferred first-line treatment of PD.
Certain hydroxylated(phenols or catechols)phenylethylamines (as such or forming part of a semi rigid/rigid ring system) are known to possess useful dopaminergic activity at least in animal models. However, their clinical use is limited because they have low or no oral bioavailability. Apomorphine is used clinically [for clinical experiences, see for example: Manson et al., Brain 124, 331 (2001) and Neef and van Laar, Clin. Pharmacokinet., 37, 257 (1999)]. Several clinical studies are ongoing with alternative delivery strategies for apomorphine, e.g. using intranasal and sublingual formulations; however, these efforts have not yet resulted in an option for the clinical treatment of PD [for general discussions, see: Stacy and Factor (Eds) Neurology, 62 (Supplement 4), S1 (2004) and Neef and van Laar, Clin. Pharmacokinet., 37, 257 (1999)].
DA receptor agonists are able to activate the DA autoreceptors as well as the postsynaptic DA receptors. The effects of autoreceptor stimulation appear to predominate when, for example, apomorphine is administered at low doses, whereas at higher doses the attenuation of DA transmission is outweighed by the enhancement of postsynaptic receptor stimulation. The antipsychotic and antidyskinetic effects in humans of low doses of, for example, apomorphine are likely due to the autoreceptor-stimulator properties of this DA receptor agonist. This body of knowledge indicates that DA receptor stimulants with a high selectivity for central nervous DA autoreceptors would be valuable in treating psychiatric disorders.
Diseases in which an increase in dopaminergic turnover may be beneficial include geriatric diseases as well as bradykinesia. DA receptor stimulants can have an effect in depressed patients, and can be used in the treatment of obesities as an anorectic agent. DA receptor stimulants can improve minimal brain dysfunction (MBD), narcolepsy, and negative and cognitive symptoms of schizophrenia. Restless leg syndrome and periodic limb movement disorder are other indications which are clinically treated with DA-agonists [for a discussion, see: Lesage and Hening, Seminars in Neurology, 24, 249 (2004)]. In addition, impotence and erectile dysfunction are also likely to be improved by treatment with a DA-agonist (in both women and men). In this context, it is noteworthy that apomorphine when given sublingually is used clinically to improve erectile dysfunction in men.
Clinical studies of therapies using L-DOPA and the D2 agonist Pramipexole in Huntington's disease [a neurodegenerative disorder caused by an expanded trinucleotide repeat (CAG) located at the 5′ end of the 1T15 gene] have shown promising results; thus, treatment of Huntington's disease is another potential application of the compounds of the invention. Other neurodegenerative disorders caused by an expanded CAG trinucleotide repeat may also be treatable by the compounds of the invention.
DA is involved in regulation of the cardiovascular and renal systems, and accordingly, renal failure and hypertension can be considered further indications for the compounds of the invention.
Furthermore, DA receptor agonists are used in the treatment of hyperprolactinemia to lower the amount of prolactin in the blood [For a recent review see: Chanson, P. et al, Annales d'Endocrinologie 68(2-3), 113 (2007)]. One example of such a DA receptor agonist is the selective D2 agonist quinagolide (Norprolac®). Therefore, hyperprolactinemia can also be considered as an additional indication for the compounds of the invention.